Project Summary: A novel paracrine role for GLP-1 in the islet The preproglucagon gene (Gcg), expressed in the intestine, the pancreas, and a small cluster of neurons in the hindbrain, encodes multiple peptides in a tissue-specific manner. One of these peptides, glucagon like peptide-1 (GLP-1) increases following meals, functions to stimulate insulin secretion, and is essential for normal glucose tolerance. The dogma is that intestinally-derived GLP-1 acts as a hormone binding to pancreatic GLP-1 receptors (GLP-1r) to stimulate insulin secretion. However, in both human and rodent models, there is emerging in vitro and pathophysiological evidence to support the production of GLP-1 in the endocrine pancreas. Our preliminary data reveal in vivo evidence that not only does a pancreatic source of GLP-1 exist, but that this pool of active peptide plays a necessary physiological role in normal glucose tolerance. These data represent a paradigm shift in our understanding of the GLP-1 system. In this model, the acute insulinotropic effects of endogenous GLP-1 are paracrine rather than endocrine, derived from islet ?- cells and acting on ?-cell GLP-1r to stimulate insulin secretion. This model would address many of the questions faced when arguing that GLP-1 has classical endocrine action on the islets. Limited by rapid intravascular metabolism, the plasma concentrations of GLP-1 are relatively low and are only modestly elevated during meal ingestion. Interestingly, there are multiple experimental models available that manipulate plasma and/or pancreatic GLP-1 and even more interesting is that two, in particular, represent extremes in ?- cell function. Both streptozotocin-induced diabetes and bariatric surgery raise plasma and/or pancreatic GLP-1 with opposite effects on islet function. In this proposal, we will use our unique genetic models combined with pharmacological and surgical interventions in order to advance the understanding of the in vivo role of pancreatic GLP-1 and in the process will help elucidate many controversies surrounding this source of GLP-1. We propose to do this in 2 specific aims: Specific Aim 1 is focused on understanding the physiological function of pancreatic GLP-1 and will test the hypothesis that pancreatic GLP-1 stimulates insulin secretion and production through paracrine mechanisms. Specific Aim 2 is focused on the pharmacological function of pancreatic GLP-1 and will test the hypothesis that the contribution of pancreatic GLP-1 to ?-cell function increases in bariatric surgery and streptozotocin-induced diabetes.